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Review Article

Why brachytherapy boost is the treatment of choice for most women with locally advanced cervical carcinoma? Karine A. Al Feghali, Mohamed A. Elshaikh* Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI

ABSTRACT

The standard treatment approach for women with locally advanced cervical carcinoma is definitive radiation treatment with concurrent cisplatin chemotherapy. Radiation treatment is typically external beam radiation therapy to the pelvis followed by intracavitary brachytherapy (BT) boost to the cervix. Numerous studies confirmed very successful outcomes with this approach. In recent years, however, the use of BT to boost the cervix in women with cervical carcinoma was reported to be on the decline. With the advent of advanced external beam radiation therapy techniques, few attempts have been made to substitute the BT boost with stereotactic body radiation therapy or intensity-modulated radiation therapy techniques, but there is a lack of prospective data to justify the routine use of these alternate boost techniques. The aim of this review is to highlight the differences between the use of stereotactic body radiation therapy or intensity-modulated radiation therapy, in lieu of intracavitary BT boost in women with locally advanced cervical cancer, and to argue that BT seems to be truly irreplaceable at the present time and with the knowledge and expertise accumulated to date. Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Keywords:

Cervical cancer; Radiation therapy; Brachytherapy; Intensity-modulated radiation therapy; IMRT; Stereotactic body radiation therapy; SBRT

Introduction According to the estimated statistics for the year 2015, cervical cancer is the third most common gynecologic malignancy and the third most common cause of death among patients with gynecologic cancers in the United States (1,2). The morbidity and mortality of cervical cancer in developed countries have dramatically decreased over the past 80 years, coinciding with the emergence of successful screening methods and effective treatment of preinvasive lesions (3). In developing countries, however, cervical cancer still constitutes the second most common cause of cancer deaths in women among all cancer types (second only to breast cancer) (4,5). Around 85% of the global burden of cervical cancer occurs in the developing countries, where access to screening remains suboptimal (5).

Received 6 October 2015; received in revised form 23 November 2015; accepted 7 December 2015. * Corresponding author. Department of Radiation Oncology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202. Tel.: þ1 (313)-916-1015; fax: þ1 (313)-916-3664. E-mail address: [email protected] (M.A. Elshaikh).

The standard treatment approach for patients with locally advanced cervical cancer is definitive external beam radiation therapy (EBRT) to the pelvis with concurrent cisplatin chemotherapy (6), followed by brachytherapy (BT) boost to the cervix. With such combined modality approach and with contemporary BT techniques, local control rates are excellent and range between 79% and 96% (7e12), and overall survival rates range from 58% to 80% for patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB2eIIB cervical carcinoma and up to 50% for patients with Stage IIIeIVA disease, according to statistics from the American Cancer Society and to contemporary studies (7,8,13). Multiple studies, including Patterns of Care studies, have consistently shown that BT used as boost after EBRT significantly improves survival and that treatment of the central disease (vaginal, cervix, medial parametria) is highly dependent on the dose given by the intracavitary sources through BT (14e18). However, the use of BT to boost the cervix in women with cervical carcinoma was recently reported to be on the decline (19,20). This trend is not unique to cervical cancer and was also reported in other gynecologic sites, such as the vaginal cancer (21). With the advent of

1538-4721/$ - see front matter Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2015.12.003

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advanced EBRT techniques, attempts have been made to substitute the BT boost with stereotactic body radiation therapy (SBRT) or intensity-modulated radiation therapy (IMRT) techniques. The aim of this review was to highlight the differences between the use of SBRT and IMRT, in lieu of intracavitary BT boost in women with locally advanced cervical cancer, and to argue that BT seems to be truly irreplaceable at the present time and with the knowledge and expertise accumulated to date.

Methods and materials A search of the literature was conducted using the electronic databases MEDLINE and PubMed with search dates between 1946 and July 2015. No limits for language were applied. Search terms included ‘‘cancer of the uterine cervix’’ (or ‘‘uterine cervical neoplasms’’ as a MeSH term), ‘‘brachytherapy,’’ ‘‘intensity-modulated radiation therapy’’ (‘‘Radiotherapy, intensity-modulated’’ as a MeSH term), and ‘‘stereotactic body radiation therapy’’ (‘‘Radiosurgery’’ as a MeSH term). The search was also guided by reference lists of published studies and proceedings of meetings, such as abstracts from the American Society for Radiation Oncology, the European Society for Therapeutic Radiology and Oncology, and the American Brachytherapy Society. Included studies were clinical studies in which patients with carcinoma of the uterine cervix were selected and were treated with IMRT or SBRT as a boost following EBRT, as part of their definitive treatment. Dosimetric studies, in which SBRT or IMRT plans were devised and compared (or not) with intracavitary or interstitial BT plans, were also included. Studies that included both patients with endometrial cancer and patients with cervical cancer were not excluded. Studies in which patients were treated with IMRT or SBRT, but not as part of their boost treatment, were excluded and studies in which all the patients had recurrent cervical carcinoma. Excluded also were studies in which boost treatment was used in the adjuvant and not in the definitive setting in all the patients. BT and its outstanding legacy of success Many decades of success have undoubtedly rendered BT the ultimate form of boost in the definitive treatment for locally advanced cervical carcinoma. Over the past 100 years, BT techniques have evolved tremendously from the Paris system, the Stockholm systems in the 1920s (18), to the predecessors of modern-day BT, the Manchester system in the 1930s, which introduced standard dose calculations using Points A and B (22,23), as well as the Fletcher (M.D. Anderson) system in the 1940s (24). In the 1960s, a search for radium substitute materials such

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as Cs, I, and Ir was undertaken, concomitantly with the development of remote afterloading by Henschke et al. (25,26), which allowed for safer BT treatments. The transition from low-dose-rate to high-dose-rate (HDR) BT also led to a relatively easier treatment and improved treatment dose optimization, with improved patients’ and operators’ convenience, while maintaining similar survival, pelvic recurrence rates, and comparable complication rates (27e29). Lately, in the past 15 years, the two-dimensional treatment planning has given way to image-based BT (IBBT), CT-based, or MRI-based BT. In 2005, the Gynecological Groupe Europeen de Curietherapie/ European Society for Therapeutic Radiology and Oncology group issued recommendations on target delineation using MRI-contoured target and organs at risk (OAR) volumes and on doseevolume parameters to be reported (30,31). IBBT has allowed optimization of prescription dose and limitation of dose to OAR, as well as provided radiation oncologists with the opportunity to adapt the dose, taking into account the different patterns of tumor shrinkage (32). It was therefore possible to move from prescription of dose to the empirical Point A to prescription to a well-defined three-dimensional target, ‘‘the sculpted pear,’’ leading to substantial improvement in target coverage and doseevolume histogram parameters (33e35). IBBT achieved excellent results, with local control rates of 95e100% at 3 years in limited IBeIIB cervical cancer patients and 85e90% in large IIB/III/IV disease, as reported in a single institutional study conducted in Vienna which included 156 patients (8). A summary of some contemporary studies with excellent local control after BT in women with cervical carcinoma is included in Table 1 (7e12). The European study on MRI-guided Brachytherapy in locally Advanced Cervical cancer, a multicenter prospective observational study, endorsed by the Groupe Europeen de Curietherapie/European Society for Therapeutic Radiology and Oncology, aims at establishing a benchmark for clinical outcomes with IBBT. Preliminary results were presented at the European Society for Therapeutic Radiology and Oncology meeting in 2012 (36) and at the 2015 American Society for Radiation Oncology meeting (37). Another important advance is the use of positron emission tomography in BT treatment optimization. A systematic review on that topic showed that positron emission tomographyeoptimized plans displayed better target coverage than conventional plans (38). The 5-year rates of late Grade 3e4 treatment-related morbidity in recent studies using MRI-based adaptive BT were low and range from only 2e8% for bladder and rectum (7e12) (Table 1). A Nordic study comparing CT-based planning with image-guided adaptive BT demonstrated a 50% reduction in moderate and severe late morbidity when using the latter (39). Technical advances,

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Table 1 Examples of some modern studies for image-based brachytherapy as a boost in the radiation treatment of women with cervical carcinoma

Study

No. of Tumor patients stage

Median followup Local BT dose D90 HR CTV time (Gy  SD) (months) control rates rate

Survival

Grade 3 toxicities or higher

CastelnaudMarchand et al. (7) Potter et al. (8)

225

IB1eIVA PDR

80.4  10.3

38.8

86.4% (at 3 years) OS: 76.1% (at 3 years); 18 Late GI and GU DFS: 71.6% (at 3 years) toxicities (in 14 patients)

156

IB1eIVA HDR

80.4  10.3

42

95% (at 3 years)

Kang et al. (9)

97

IBeIVB

HDR

d

50

Tan et al. (10)

28

IB1eIIIB HDR

d

23

Charra-Brunaud 117 et al. (11)

IB1eIIIB PDR

73.1  11.3

24.3

Simpson et al. (12)

IB1eIVA HDR

86.3  8.1

17

76

OS: 68% (at 3 years); CSS: 74% (at 3 years)

3 Patients with bladder toxicity, 5 with rectal toxicity, and 3 with vaginal toxicity 93% (at 3 years) PFS: 80% (at 3 years) 2 Patients with late rectal bleeding 96% (at 3 years) CSS: 81% (at 3 years) 2 Patients with abdominal pain and 1 with fistula 78.5% (at 2 years) OS: 74% (at 2 years); 1.2% Of patients with GU DFS: 60.3% (at 2 years) toxicities and 1.2% with GU and GI 94.2% (at 2 years) OS: 75% (at 2 years); 2 Patients with intractable DFS: 60.3% (at 2 years) nausea and vomiting, 3 with neutropenic fever, and 1 with stricture

BT 5 brachytherapy; D90 HR CTV 5 dose delivered to 90% of the high-risk clinical target volume; PDR 5 pulsed-dose rate; OS 5 overall survival; DFS 5 disease-free survival; GI 5 gastrointestinal; GU 5 genitourinary; HDR 5 high dose rate; CSS 5 cancer-specific survival; PFS 5 progression-free survival.

with the use of IBBT, have thus mitigated most of the late treatment-related morbidities associated with BT. The concerning decline in BT use Despite all these advances and despite proven significant benefit, a population-based analysis by Han et al. looking at trends of BT use in patients with Stage IB2eIVA cervical cancer in the United States, using Surveillance, Epidemiology, and End Results data, revealed an alarming decline in BT use, from 83% in 1988 to 43% in 2003. It also showed significant geographic disparities in the use of BT in the United States. Interestingly, in this same study, BT use was again demonstrated to be associated with significantly better cancer-specific survival (64% vs. 52%) and overall survival (58% vs. 46%) at 4 years (19). Another study, based on the National Cancer Data Base, analyzed boost treatment in patients with Stage IIBeIVA cervical cancer treated from January 2004 to December 2011 and showed a decline in BT use in this period, with a parallel increase in the use of highly conformal external beam radiation techniques, including IMRT and SBRT, despite scarcity of published data on the matter. Results from the National Cancer Data Base revealed that BT use decreased from 97% to 86% from 2004 to 2011, whereas IMRT or SBRT use concomitantly increased from 3.3% to 13.9%. It also showed that IMRT or SBRT boost resulted in inferior overall survival (hazard ratio 5 0.86, p ! 0.01) as compared with BT. Interestingly enough, this survival detriment appeared to be stronger than that associated with chemotherapy omission (20).

Many factors might have contributed to the reported decline in BT; Surveillance, Epidemiology, and End Result underreporting of BT use as argued by Smith and Eifel (40), decreasing BT training and expertise of radiation oncologists (41), emergence of high-tech external beam radiation that are trying to replace BT, changes in reimbursement, and failure to refer patients to centers with better BT expertise (42). For some patients, BT could also entail invasive cervical sleeve insertion, some sedation, or anesthesia with its potential complications and requires careful and cumbersome quality assurance measures, which may constitute limiting factors to its successful implementation. Furthermore, BT implant quality is critical and should be performed in a precise and reproducible manner. Failure to do so has detrimental impact on outcomes: Inappropriate placement of packing has been shown to result in lower disease-free survival in a review of data from the Radiation Therapy Oncology Group protocols 0116 and 0128; in addition, displacement of ovoids in relation to the cervical os and unacceptable symmetry of ovoids to the tandem have been associated with both an increased risk of local recurrence and with a lower disease-free survival (43). BT therefore appears to highly rely on physicians’ skills and training, and it has been demonstrated that high-volume centers have better patient outcomes (19). The American Brachytherapy Society issued comprehensive guidelines for HDR BT (44), as well as for low-dose-rate BT (45), to allow for optimal tumor coverage and safe procedures. In a study by Smith et al. looking at a cohort of 1508 insured women under 65 years of age in an employment-

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Table 2 Published studies using stereotactic body radiation therapy as a boost in the radiation treatment of women with cervical carcinoma

Study Haas et al. (47) Hsieh et al. (48)

No. of Tumor patients stage

SBRT technique

6

IIBeIVA

CyberKnife

9

IIBeIVA

Tomotherapy

Marnitz 11 et al. (49) Kubicek 7 et al. (50)

IIBeIIIB

CyberKnife

Mantz 28 et al. (51)

Boost dose

Median followup time (mo) Local control rates Survival

20 Gy in 14 5 fractions 16e27 Gy 13 in 5e9 fractions

30 Gy in 5 fractions IIIB and CyberKnife 15e27.5 Gy recurrent in 3e5 fractions 40 Gy in 5 IB1eIIIB Linear accelerator fractions NR

6 4

51

100% (at last F/U) OS and DFS: 100% (at last F/U) 77.8% (at 3 years) OS: 46.9% (at 3 years); DFS: 25.9% (at 3 years)

Grade 3 toxicities or higher None

1 Patient with diarrhea, 3 with rectal bleeding, and 1 with fistula formation 100% (at last F/U) OS and DFS: 100% 4 Patients with (at last F/U) hematologic toxicity 73% (at last F/U) OS: 57.1% (at last F/U); 1 Patient with rectal DFS: 42.8% bleeding (at last F/U) 90.9% for Stages DFS: 81.8% for Stages None IeII, and 66.7% IeII and 50% for for Stage III Stage III (at 5 years) (at 5 years) NR

SBRT 5 stereotactic body radiotherapy; F/U 5 followup; OS 5 overall survival; DFS 5 disease-free survival; NR 5 not reported.

based health care claims database did not show a decrease in the frequency of BT from 1999 to 2011. In this study, only 2.5% of patients and 0.2% of patients received IMRT and SBRT, respectively, in the setting of BT omission (46). BT vs. SBRT and IMRT: comparative studies and challenges Eight studies were found in the literature on the use of SBRT as an alternative boost treatment for cervical carcinoma (47e54) (Tables 2 and 3) and six studies about IMRT (55e60) (Table 4). Few studies in the literature tackled EBRT boost with IMRT or SBRT in the setting of definitive treatment of locally advanced cervical cancer in patients who were otherwise eligible for BT. Most of the studies that were encountered during the search included patients with recurrent cervical cancer, or patients who were not candidates for BT, for various reasons. Some included heterogeneous patient populations with different gynecologic malignancies (50,51,59,60) and did not focus solely on cervical cancer. Not all patients in these studies received cisplatin chemotherapy or the status of chemotherapy (received or not) was not reported (50). In addition, many studies were focused only on dosimetric, rather than clinical comparison analysis between BT and IMRT or SBRT. We could only find five studies with SBRT (47e51) and only one with IMRT (60) reporting patients’ clinical outcomes. Most studies had a very small sample size (largest sample size across all studies was 28 (51)), short followup times, and most were retrospective in nature. Dosing regimens and fractionation varied widely from one study to the other (Tables 2e4). Studies also used different parameters in their comparative dosimetric analyses, making it difficult to perform across-studies comparisons and dose-toxicity evaluation.

All the studies reporting clinical outcomes showed a trend toward good local control with SBRT and IMRT (73e100%) (47e51,60). However, the definition of the target volumes was inconsistent across the studies: CT, MRI, and physical examinations were used in most articles to delineate the gross tumor and clinical target volume (CTV). In some, CTV for the boost treatment was defined as the whole cervix (or gross disease and subclinical extension) and any residual disease outside the cervix (49,50,52,59). In other studies, CTV was not clearly defined in the manuscript (47). In the dosimetric study by Low et al. (56), the target volume was defined as Point A isodose surface. To various CTV targets, median dose equivalents in 2-Gy fractions, or EQD2, were in the range of 73e 104 Gy for studies using SBRT as boost (when added to 45e50.4 Gy of whole-pelvis radiation treatment, depending on each study) (47e51) and in the range of 75e80 Gy in the clinical study using IMRT as boost (60). In a study by Barraclough et al., non-IMRT, non-SBRT EBRT boost was shown to result in much poorer local control, whereby central recurrences were identified in 16 of the 44 patients (33%) included (61). Late Grade 3 gastrointestinal toxicities were observed in two of the studies on SBRT included in this review: 3 of 9 patients in the Hsieh et al. study had rectal bleeding and one had rectal fistula formation (48), and 1 of 7 patients in the Kubicek et al. (50) study suffered from rectal bleeding as well. Other Grade 3 or higher toxicities reported were hematologic [4 of 11 patients in the study by Marnitz et al. (49)]. In the series on IMRT as boost treatment by Huang et al. (60), late Grade 3 or higher toxicities included cystitis (2 patients), enteritis (1 patient), and fistula formation (1 patient). As Patil et al. (62) argued in their letter to the editor, comparison of treatment plans may be misleading if proper target delineation (using MRI for BT) is not undertaken.

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Table 3 Published dosimetric studies comparing stereotactic body radiation therapy and brachytherapy boost treatments in women with cervical carcinoma Dosimetric analysis Study

No. of patients Tumor stage SBRT technique

Cengiz et al. (52)

11

IIB

Neumann et al. (53)a 11

IIBeIIIB

Palmgren et al. (54) (abstract only)

NR

12

Median Boost dose CI (range)

Dose distributions to OAR

CyberKnife

28 Gy in 4 1.27 (1.03e1.38) - 25% isodose line for rectum (sig. better for fractions HDR BT, p ! 0.05) - 100% dose volume for OAR (rectum, bladder, and sigmoid colon) larger in HDR BT plans ( p ! 0.05). - D2cc for bladder and rectum favoring SBRT CyberKnife, using gold 30 Gy in 5 NR - RRS25 exceeded tolerable dose constraints for fiducial markers fractions the walls of the critical OAR. - D2cc for bladder, rectum, and sigmoid similar for RRS70 and MRI-guided BT. CyberKnife, using gold 28 Gy in 4 1.2  0.04 - D2cc for bladder, rectum, sigmoid, and bowel fiducial markers fractions similar for SBRT and BT

SBRT 5 stereotactic body radiotherapy; CI 5 conformity index; OAR 5 organs at risk; HDR 5 high dose rate; BT 5 brachytherapy; NR 5 not reported; RRS 5 robotic radiosurgery; D2cc 5 dose received by 2 cc of the considered target structure. a This study compares MRI-guided BT (high-tech BT based on EMBRACE protocol) to SBRT. In this study, two planned boost techniques for SBRT were performed: one of them emulating BT-like inhomogeneous dose distributions (RRS70), whereby prescribed isodose 70% 5 30 Gy, and the second with prescribed isodose 25% 5 30 Gy, allowing higher maximum doses (RRS25).

Most comparative studies reported in this review did not use IBBT as a comparator, but rather used conventional Point Aebased BT techniques. In the study by Low et al. (56), applicator-guided IMRT was benchmarked against noneMRI-based BT, and Point A dosimetry was used instead of target volumeebased dosimetry. Similarly, in the study by Cengiz et al. (52), an unfair comparison between advanced SBRT with Cyberknife and traditional BT techniques with prescription to Point A

was undertaken, showing improved target coverage with SBRT. In the only study where MRI-guided BT technique was compared with IMRT and IMPT (intensitymodulated proton therapy), both of these high-tech EBRT techniques were found to be inferior in terms of target coverage and OAR avoidance (55). In addition, another study showed that interstitial BT was superior to IMRT for patients whose anatomy or tumor did not allow intracavitary BT (58).

Table 4 Published dosimetric studies comparing intensity-modulated radiation therapy and brachytherapy boost treatments in women with cervical carcinoma

Study

No. of patients Tumor stage Dose

Dosimetric analysis Target coverage

Dose distributions to OAR

GTV doses were mostly lower for both IMRT and IMPT vs. BT with 3e5 mm margins More conformality/homogeneity with the AGIMRT plansb -More conformality/homogeneity with the AGIMRT plans. -Larger volume of tumor covered by the prescription isodose surface compared with BT (mean of 90.0% vs. 58.2%; p 5 0.005). -Better target coverage with IBT vs. IMRT.

Bowel volumes receiving 60 Gy (EQD2) were approximately twice as large for IMRT compared with BT AGIMRT improved rectal sparing relative to BT

Georg et al. (55)a

9

IIBeIIIB

28 Gy in 4 fractions

Low et al. (56)

3

38 Gy in 6 fractions 39 Gy in 6 fractions

33 Gy in 13 fractions 31 Gy in 5 fx -More homogeneity with tomotherapy. -Nonsignificant higher D90 with tomotherapy vs. BT.

Wahab et al. (57)

10

Locally advanced IB2eIII

Sharma et al.(58)

12

IIBeIIIB

Gielda et al. (59)c

4

IIAeIIIB, recurrent

Percentages of bladder and rectal volume exceeding the tolerance limit were lower with the AGIMRT plans (IMRT)

-Significantly higher doses to rectum and bladder with IMRT. -More dose to femoral heads and bowel with tomotherapy. -Slightly lower D2cc for both bladder and rectum with tomotherapy compared with BT.

GTV 5 gross tumor volume; IMRT 5 Intensity-modulated radiation therapy; IMPT 5 Intensity-modulated proton therapy; BT 5 brachytherapy; OAR 5 organs at risk; EQD2 5 equivalent dose in 2 Gy; AGIMRT 5 Applicator-guided intensity-modulated radiation therapy; IBT 5 interstitial brachytherapy; D90: minimum dose to 90% of the considered target structure; D2cc: dose received by 2 cc of the considered target structure. a This is the only study comparing MRI-guided BT (high-tech BT) to IMRT/IMPT. b This applicator was used to provide spatial registration and immobilization of gynecologic organs. c Helical tomotherapy was compared with interstitial brachytherapy in this study.

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The argument of high-tech EBRT proponents that IMRT or SBRT can produce more homogeneous dose distributions is not meaningful in the boost treatment phase for cervical cancer, as the aim is usually to concentrate the dose on central and paracentral disease where most of the recurrences occur and where hypoxic cells abound and not necessarily have a homogeneous dose throughout. The inverse square dose falloff serves this purpose well. For instance, in the dosimetric comparative study by Sharma et al. (58), the maximal dose to the planning target volume (PTVmax) dose was significantly higher with BT than with IMRT (126.34 Gy vs. 50.79 Gy) and PTVmin significantly lower (17.63 Gy vs. 27.99 Gy). This heterogeneity, signifying more hot and cold spots, helps in better controlling the tumor while sparing OAR and should not be considered a disadvantage of BT. High-dose regions in the center of the PTV could reach O300% of the prescription dose adjacent to the BT sources and most probably result in higher probability of local control. The clinical consequences of delivering a homogeneous dose of 85e 90 Gy in total to the tumor volume with SBRT or IMRT, without the high central doses, are unknown. It is clear from all the studies included in this review that achieving inhomogeneity with inverse optimization algorithms, and thus mimicking BT dose distributions, is not an easy task. However, it should be noted that optimal target dose heterogeneity with BT has not been elucidated and is yet to be determined by future studies. In addition, the exact dose needed and whether dose de-escalation could be attempted are still topics under investigation. Nowadays, dose planning aims vary from 80 Gy to more than 85 Gy in total EQD2 to high-risk clinical target volume. One study found that a dose of O87 Gy to the high-risk clinical target volume in HDR BT resulted in local recurrence rates of only 4% vs. 20% for D90 ! 87 Gy, for tumor size greater than 5 cm (63). The feasibility of achieving such high doses with IMRT was tested in a dosimetric study at the University of Chicago. It showed that IMRT could potentially achieve doses ranging from 79 Gy (if a 1-cm PTV expansion was used) to 84 Gy (with expansion of 0.25 cm) (64). The simultaneous integrated boost approach with IMRT has also been tried at the University of Colorado, based on the premises that even a modest increase in fraction size would increase the cell kill (65). This approach would allow a reduction in the overall treatment time and therefore mitigate tumor cell repopulation, which could be radiobiologically advantageous. Twenty-two patients with FIGO stage IIIAeIVA were treated using this concomitant boost technique, and results showed encouraging local control rates (81% at 7 years). Serious late toxicity included bowel injury requiring colostomy in 8 of the 22 patients was reported tempering the good local control rates (66). The high-tech EBRT techniques have been advocated in case of bulky tumors or tumors with a particular geometry,

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where intracavitary BT alone cannot achieve optimal dose distribution. However, by using differential loading, interstitial BT could complement intracavitary BT successfully in these special settings or be used on its own when the patient’s anatomy cannot accommodate an intracavitary applicator, with acceptable outcomes, and durable pelvic control (67e71). Another important challenge for the use of EBRT techniques as an alternative to BT is interfraction and intrafraction internal motion. If EBRT techniques are to be used, then accurate localization of the tumor and OAR is primordial, and reproducibility is key. A study from the University of California at San Diego showed that through a course of IMRT, cervical motion averages 3 mm in any direction, but maximal movement can reach 18 mm from baseline (72). To circumvent the issue of internal motion and to minimize geometric miss, investigators used different methods. Real-time tracking using fiducial markers for SBRT was used by some investigators (47,49,50,52), whereas others developed an applicator-guided IMRT (56,57). In the latter technique, an applicator was used to localize the cervix and uterus, to reproducibly position OAR, and to spatially register internal organs for planning and treatment. There was no mention, however, of validation of this tool. All these attempts to remedy the problem of internal motion need to be thoroughly evaluated before being routinely used in practice. Interfractional variation in OAR volume and positioning could be accounted for in BT using deformable image distribution and dose composition (73,74). Another challenge is the need for margins in EBRT to account for setup and internal motion. The close proximity of critical organs makes this expansion of target volumes more challenging and leaves no room for error in planning. This problem does not apply to BT, as the BT apparatus is almost fixed to the target, and as the internal organs move, the BT system moves along with them. This feature of BT has been termed ‘‘natural gating.’’ Portal image-based verification of positioning, used in three-dimensional conformal radiation therapy, is not applicable in the treatment of cervical cancer, as the tumor is not fixed relative to bony anatomy. Finally, the use of IMRT or SBRT entails more low-dose radiation to surrounding normal tissues, with a hypothetical increased risk of secondary malignancies as compared with BT especially in younger patients with cervical carcinoma.

Conclusion Citing the title of an article by Petereit et al. (75), the question ‘‘Brachytherapy, where has it gone?’’ seems to depict the current situation accurately. Despite the rising popularity of sophisticated external beam radiation techniques such as SBRT and IMRT, numerous studies suggest that BT remains the sole means for delivering very high doses to the center of the

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tumor while sparing nearby OAR. The routine use of image-based (CT or MRI) has allowed better assessment of applicator positioning and has potentially rendered technical accuracy easier. Efforts should focus on continued education of radiation oncologists on IBBT techniques to improve cancer care of patients with cervical carcinoma. The recent decline in utilization of BT in the treatment of women with cervical carcinoma has been associated with worse outcomes. In regard to highly conformal EBRT, for example, IMRT and SBRT, many concerns remain to be addressed: Are doses achieved with IMRT or SBRT high enough to provide adequate tumor control? Is inhomogeneity really necessary or would homogeneous dose distributions achieved with EBRT techniques be satisfactory? How to overcome the issue of internal organ motion when using IMRT or SBRT? Considering organ motion, what is an adequate PTV margin? We recognize, however, that for patients whose anatomy precludes BT use, or who have medical contraindications to anesthesia/sedation, or refuse BT, a conformal EBRT boost using IMRT or SBRT may be a reasonable alternative. Future studies should focus on clinical end points and not only dosimetric end points, mainly local control, survival, acute, and long-term toxicities. At present, it would be inappropriate to routinely replace BT with any of the EBRT techniques to boost the cervix in patients with locally advanced cervical cancer who have no contraindications to BT.

References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5e29. [2] Barakat RR, Markman M, Randall M. Principles and practice of gynecologic oncology. 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009. [3] Quinn M, Babb P, Jones J, et al. Effect of screening on incidence of and mortality from cancer of cervix in England: evaluation based on routinely collected statistics. BMJ 1999;318:904e908. [4] Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87e108. [5] Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359eE386. [6] Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCMAC). Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database Syst Rev 2010; CD008285. [7] Castelnau-Marchand P, Chargari C, Maroun P, et al. Clinical outcomes of definitive chemoradiation followed by intracavitary pulsed-dose rate image-guided adaptive brachytherapy in locally advanced cervical cancer. Gynecol Oncol 2015;139:288e294. [8] Potter R, Georg P, Dimopoulos JCA, et al. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol 2011;100:116e123.

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